Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris
Jinmin Lee, … , Michael C. Milone, Aimee S. Payne
Jinmin Lee, … , Michael C. Milone, Aimee S. Payne
Published August 20, 2020
Citation Information: J Clin Invest. 2020;130(12):6317-6324. https://doi.org/10.1172/JCI138416.
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Concise Communication Autoimmunity

Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris

Abstract

Desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) expressing the pemphigus vulgaris (PV) autoantigen DSG3 fused to CD137-CD3ζ signaling domains, represent a precision cellular immunotherapy approach for antigen-specific B cell depletion. Here, we present definitive preclinical studies enabling a first-in-human trial of DSG3-CAART for mucosal PV. DSG3-CAART specifically lysed human anti-DSG3 B cells from PV patients and demonstrated activity consistent with a threshold dose in vivo, resulting in decreased target cell burden, decreased serum and tissue-bound autoantibodies, and increased DSG3-CAART engraftment. In a PV active immune model with physiologic anti-DSG3 IgG levels, DSG3-CAART inhibited antibody responses against pathogenic DSG3 epitopes and autoantibody binding to epithelial tissues, leading to clinical and histologic resolution of blisters. DSG3 autoantibodies stimulated DSG3-CAART IFN-γ secretion and homotypic clustering, consistent with an activated phenotype. Toxicology screens using primary human cells and high-throughput membrane proteome arrays did not identify off-target cytotoxic interactions. These preclinical data guided the trial design for DSG3-CAART and may help inform CAART preclinical development for other antibody-mediated diseases.

Authors

Jinmin Lee, Daniel K. Lundgren, Xuming Mao, Silvio Manfredo-Vieira, Selene Nunez-Cruz, Erik F. Williams, Charles-Antoine Assenmacher, Enrico Radaelli, Sangwook Oh, Baomei Wang, Christoph T. Ellebrecht, Joseph A. Fraietta, Michael C. Milone, Aimee S. Payne

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Figure 3

DSG3-CAART reverses rising serum antibody titers and improves blistering in a PV active immune model.

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DSG3-CAART reverses rising serum antibody titers and improves blistering...
DSG3–/–DSG1tg/tg (DSG3-KO) mice were immunized with rhDSG3, followed by splenocyte transfer into syngeneic RAG2–/– mice. Twenty days after adoptive transfer of splenocytes, 10 and 5 mice were treated with DSG3-CAART or NTD T cells, followed by euthanasia on day 39 (5 mice in each treatment group) or day 69 (5 DSG3-CAART–treated mice), or earlier based on humane endpoints. (A and B) DSG3-CAART (images 6–15) improves hair loss, erosions, and histologic acantholysis (arrows), which persists in NTD-treated mice (images 1–5). Scale bars: 200 μm. (C) Mouse reagents were normalized for use in the human clinical DSG3 ELISA to calculate an anti-DSG3 antibody index value (RU/mL) for all mice with remaining serum samples. Serum anti-DSG3 antibody levels in the active immune model match or exceed those observed in human PV patients. (D) ELISA (mean OD with standard deviation) normalized to week 3 values indicates that DSG3-CAART treatment reduces serum anti-DSG3 antibody titers during the period of DSG3-CAART persistence. (E) T cell persistence by flow cytometry of peripheral blood, weeks 6–8 after splenocyte transfer.